Cysteine-rich granulin-3 rapidly promotes amyloid-ß fibrils in both redox states.
Biochem J
; 476(5): 859-873, 2019 03 12.
Article
en En
| MEDLINE
| ID: mdl-30782973
ABSTRACT
Granulins (GRNs 1-7) are cysteine-rich proteolytic products of progranulin (PGRN) that have recently been implicated in neurodegenerative diseases including frontotemporal dementia (FTD) and Alzheimer's disease (AD). Their precise mechanism in these pathologies remains uncertain, but both inflammatory and lysosomal roles have been observed for GRNs. Among the seven GRNs, GRN-3 is well characterized and is implicated within the context of FTD. However, the relationship between GRN-3 and amyloid-ß (Aß), a protein relevant in AD pathology, has not yet been explored. To gain insight into this mechanism, we investigated the effect of both oxidized and reduced GRN-3 on Aß aggregation and found that both GRN-3 (oxidized) and rGRN-3 (reduced) bind to monomeric and oligomeric Aß42 to promote rapid fibril formation with subtle rate differences. As low molecular weight oligomers of Aß are well-established neurotoxins, rapid promotion of fibrils by GRN-3 mitigates Aß42-induced cellular apoptosis. These data provide valuable insights in understanding GRN-3's ability to modulate Aß-induced toxicity under redox control and presents a new perspective toward AD pathology. These results also prompt further investigation into the role(s) of other GRNs in AD pathogenesis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
/
Péptidos beta-Amiloides
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Apoptosis
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Enfermedad de Alzheimer
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Agregación Patológica de Proteínas
/
Granulinas
Límite:
Humans
Idioma:
En
Revista:
Biochem J
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos